We have identified numerous porphyrins and phthalocyanines (Pc) and their metal chelates which are very active against the human immunodeficiency virus (HIV-1) and, in addition, have little toxicity. We have found that porphyrins and Pcs act via a variety of biochemical mechanisms. Therefore, we propose to synthesize a large number of these macrocycles both to identify potential therapeutic agents and to develop an understanding of their mode of action through structure-activity correlations. Porphyrins. We have six goals in developing porphyrins and metalloporphyrins as anti-HIV therapeutic agents. (1) Overall, the sulfonato derivatives of tetraphenylporphyrin (TPP) have the highest activity and lowest toxicity in studies to date. We propose to synthesize and characterize additional members of this class. (2) Very limited studies on naphthalene and anthracene porphyrins have shown these to be active against HIV-1. We propose the synthesis of additional members of these classes based on our studies of TPP derivatives. (3) We propose the synthesis of various sulfonate or carboxy derivatives with the negative charge removed from the ring. (4) Some zwitterionic porphyrins, as yet only incompletely characterized, have excellent activity. We propose to synthesize and characterize zwitterionic porphyrins. (5) We propose the synthesis of additional water-soluble neutral porphyrins. (6) We will synthesize new positively-charged porphyrins and continue our studies on the correlation of HIV activity and toxicity with the mode of nucleic acid binding. Phthalocyanines. We propose syntheses of specific Pc, concentration on positively-charged, negatively-charged and neutral examples with satisfactory aqueous solubility. All three charge types are active in the porphyrin series, although not all with the same biochemical mechanism. We propose to develop synthetic routes and separation techniques to obtain isometrically pure Pc. We propose to develop the analytical techniques necessary to determine isomer purity in this class of compounds. We propose the synthesis of Pcs which bind to and react with specific types of sequences in the HIV RNA. Structure-Activity Relationships. Throughout this work, we propose to continue to develop structure-activity relationships. To date, we have been able to explain the biological activities of certain classes of porphyrins and Pcs and/or develop leads based on hydrophobicity, net charge, the placement of charge and the shape of the molecule (specifically steric bulk in the axial direction. We propose to continue developing structure-activity relationships based on these parameters as well as the nature of the central metal.